Human immunodeficiency virus (HIV) immunization strategies employing conformationally-stabilized, surface-occluded peptides comprising a gp41 2F5 epitope in association with lipid
Inventors
Ofek, Gilad • Kwong, Peter D. • Wyatt, Richard • Tang, Min
Assignees
US Department of Health and Human Services
Publication Number
US-8147840-B2
Publication Date
2012-04-03
Expiration Date
2025-05-13
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Abstract
This invention relates to novel peptide immunogens that generate an immune response in mammals against HIV gp41, to pharmaceutical compositions that comprise such immunogens, and to methods of treating Immunodeficiency disease, especially HIV infection and AIDS, that employ such pharmaceutical compositions.
Core Innovation
This invention relates to novel peptide immunogens that generate an immune response in mammals against HIV gp41, pharmaceutical compositions comprising such immunogens, and methods of treating immunodeficiency diseases, especially HIV infection and AIDS, employing these compositions. The invention focuses on isolated peptides comprising at least ten contiguous amino acids of the sequence EKNEQELLELDKWASLW (SEQ ID NO:1), which bind to the broadly neutralizing anti-HIV-1 monoclonal antibody 2F5. These peptides are conformationally stabilized to maintain a three-dimensional structure corresponding to that observed when the peptide is complexed with the 2F5 antibody, and comprise a face that does not bind to the 2F5 antibody.
The problem addressed by the invention arises from the difficulty in developing an effective HIV vaccine capable of eliciting broadly neutralizing antibodies against HIV. The membrane proximal region (MPR) of the HIV gp41 spike protein, which contains the 2F5 epitope, is a target for neutralization, but is occluded and conformationally flexible, limiting immune recognition. Previous attempts to generate immunogens have failed to induce 2F5-like antibodies likely because the epitope's conformation and membrane context were not properly preserved, and the hydrophobic face of the gp41 peptide was exposed to immune recognition rather than occluded.
The invention overcomes these challenges by providing conformational stabilization of the 2F5 epitope peptide to mimic its structure when bound to the 2F5 antibody, ensuring one face of the peptide that does not bind 2F5 is occluded, for example by lipid or carbohydrate moieties, and presenting the immunogen in a membrane context such as proteoliposomes. Through structural and immunological analyses, a vaccine strategy including conformational stabilization, surface occlusion, membrane context presentation, and a prime-boost immunization approach is proposed to elicit broadly neutralizing antibodies akin to 2F5.
Claims Coverage
The independent claims cover three main inventive features involving an isolated peptide immunogen, a method of generating an immune response, and a nucleic acid construct.
Isolated peptide associated with lipid and conformationally stabilized
An isolated peptide comprising at least ten contiguous amino acids of the sequence EKNEQELLELDKWASLW (SEQ ID NO:1) that binds to monoclonal antibody 2F5. The peptide is conformationally stabilized to maintain the three-dimensional structure observed when complexed with 2F5, comprises a face that does not bind 2F5, and is associated with a lipid, preferably a phospholipid not normally found on the outer cytoplasmic membrane of human cells, and more preferably in the form of a proteoliposome. This face that does not bind 2F5 is occluded with appended groups such as carbohydrate moieties. The peptide may be stabilized by linkages like disulfide bonds or lactam bridges.
Method of generating a humoral immune response using the isolated peptide immunogen
A method of generating a humoral immune response against HIV-1 gp41 in a mammal, comprising preparing a composition of the isolated peptide immunogen as described above with a pharmaceutically acceptable carrier and administering it to the mammal, resulting in the generation of a humoral immune response against the HIV-1 gp41 envelope glycoprotein.
The claims describe an isolated, conformationally stabilized 2F5-binding peptide associated with lipid and having an occluded non-binding face; and methods of using this peptide immunogen to elicit an immune response against HIV gp41, emphasizing both peptide structure and lipid association for effective immunization.
Stated Advantages
Eliciting broadly neutralizing anti-HIV antibodies by presenting the immunogen in a conformation matching the 2F5 antibody-bound state.
Masking the non-2F5 binding face of the peptide to focus immune response and avoid off-target or ineffective antibodies.
Presenting the immunogen in a membrane context enhances antibody binding and mimics the native viral environment.
Prime-boost immunization strategies improve the specificity and effectiveness of elicited antibodies against native viral gp41.
Documented Applications
Generating an immune response in mammals against HIV gp41 for vaccine development.
Pharmaceutical compositions containing conformationally stabilized 2F5 epitope peptides associated with lipids for use in treating HIV infection or AIDS.
Methods of treating immunodeficiency diseases, especially HIV infection and AIDS, by administering these peptide-based pharmaceutical compositions.
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